Protein tyrosine kinases have been identified as key players in cellular regulation. They are involved in immune, endocrine, and nervous system physiology and pathology and thought to be important in the development of many cancers. Protein tyrosine kinases represent a diverse and rapidly expanding superfamily of protein, including both transmembrane receptor tyrosine kinases and soluble cytoplasmic enzymes also known as nonreceptor tyrosine kinases.
Receptor tyrosine kinases are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor (EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation. It has also been shown that epidermal growth factor receptor (EGFR) which possesses tyrosine kinase activity is mutated and/or over expressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors. EGFR is the archetypal member of receptor tyrosine kinase family comprised of four closely related receptors called EGFR, HER2 (human EGF-related receptor), HER3 and HER4 (Pinkas-Kramarski R, Eilam R, Alroy I, Levkowitz G, Lonai P, Yarden Y. Differential expression of NDF/neuregulin receptors ErbB-3 and ErbB-4 and involvement in inhibition of neuronal differentiation. Oncogene 1997; 15:2803-2815). All of these transmembrane receptors contain an intrinsic kinase activity that modifies tyrosine residues on the receptor itself as well as on downstream signaling molecules. This kinase activity is stimulated when members of the EGF family of growth factors bind to the receptor. Ligand-induced EGFR activation initiates a signaling cascade that activates gene expression and induces cellular responses such as cell cycle progression or differentiation. Aberrant activation of this highly regulated signaling pathway is believed to contribute to many tumorigenic processes, including enhanced cellular proliferation, protection from apoptosis, tumor cell invasion and metastasis (Huang S M, Harari P M. Epidermal growth factor receptor inhibition in cancer therapy: biology, rational and preliminary clinical results. Invest New Drugs 1999; 17:259-269).
Each receptor is composed of three domains—an extracellular ligand-binding domain, a transmembrane domain, and an intracellular tyrosine kinase domain. The active receptor is a dimmer, which can be formed by combinations of identical receptor pairs (homodimerization) or different receptor pairs (heterodimerization). EGFR has two main ligands, epidermal growth factor (EGF) and transforming growth factor (TGF). Following binding of a ligand, the receptor dimerizes, which results in activation of the intracellular tyrosine kinase. This begins a number of phosphorylation events that, in turn, initiate a cascade of intracellular signaling process.
Accordingly, it has been recognized that inhibitors of receptor tyrosine kinases are useful as a selective inhibitors of the growth of mammalian cancer cells.
Normal angiogenesis plays an important role in a variety of processes including embryonic development, wound healing and several components of female reproductive function. Undesirable or pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma. Tumor angiogenesis, the formation of new blood vessels and their permeability is primarily regulated by (tumor-derived) vascular endothelial growth factor (VEGF), which acts via at least two different receptors: VEGF-R1 (fms-like tyrosine kinase, Flt-1); and VEGF-R2 (kinase domain region, KDR/fetal liver kinase-1, Flk-1). The VEGF KDR receptor is highly specific for vascular endothelial cells (for review, see: Farrara et al. Endocr. Rev. 1992, 13, 18; Neufield et al. FASEB J. 1999, 13, 9).
VEGF is another kind of receptor protein tyrosine kinases. A large number of human tumors, especially gliomas and carcinomas, express high levels of VEGF and its receptors. This has led to the hypothesis that the VEGF released by tumor cells stimulates the growth of blood capillaries and the proliferation of tumor endothelium in a paracrine manner and through the improved blood supply, accelerate tumor growth.
It has now been found that spiro compounds of formula I, described below, are a new class of compounds that have advantageous pharmacological properties and inhibit the activity of tyrosine kinases, for example, the activity of the EGFR and VEGFR tyrosine kinases, the activity of other receptor tyrosine kinases, such as c-kit, PDGF, FGF, SRC etc. They may also be irreversible inhibitors of tyrosine kinase.
Examples of spiro compounds that are similar in structure to those of the present invention are disclosed in the following literatures: WO9510519, WO9639407, WO0153273, WO03014108, WO20026073167, JP05221947, JP2004099609, EP0341493, EP0357047, EP0623585, EP611137, JMC 37, 3344 (1994), Tetrahedron Letter, 41, 8173-8176, JACS, 119, 7615-7616 and Heterocycles, 52, 595-598 with the following structures:

Examples of non-spiro compounds of quinazoline derivatives that are similar in structure to those of the present invention are disclosed in the following patent applications: EP0357047, EP 0566226, EP 0602851, EP 0635507, EP 0635498, EP 0520722, WO9633980, WO9738983, WO9738994, WO0047212, WO0121596, WO0132651, and WO02092577.